Submissions for variant NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln)

gnomAD frequency: 0.00029  dbSNP: rs104894493

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000261496	SCV000393760	pathogenic	NR2E3-related disorder	2024-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045323	SCV001209164	pathogenic	not provided	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 76 of the NR2E3 protein (p.Arg76Gln). This variant is present in population databases (rs104894493, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive retinal dystrophy (PMID: 30324420; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5530). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NR2E3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NR2E3 function (PMID: 19823680, 19898638, 27013732). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075864	SCV001241503	pathogenic	Retinal dystrophy	2019-08-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001045323	SCV001247329	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	NR2E3: PM3:Very Strong, PM2, PM5, PP1:Moderate, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000005867	SCV001366569	pathogenic	Enhanced S-cone syndrome	2019-03-12	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001045323	SCV001447893	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449793	SCV001653074	likely pathogenic	Goldmann-Favre syndrome	2020-07-03	criteria provided, single submitter	clinical testing	The p.Arg76Gln variant in NR2E3 has been reported in at least 3 homozygous and 2 compound heterozygous individuals with retinal disorders (Haider 2000 PMID: 10655056, Schorderet 2009 PMID: 10655056, Li 2017 PMID: 28418496, Stone 2017 PMID: 28559085, Murro 2019 PMID: 30324420). It has also been identified in 0.038% (45/119410) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant has also been reported in ClinVar (Variation ID: 5530). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide evidence that this variant impacts protein function (Kanda 2009 PMID: 19898638, Roduit 2009 PMID: 19823680); however, these types of assays may not accurately represent biological function. Another variant involving this codon (p.Arg76Trp) has been identified in individuals with retinal disease, suggesting change at this residue may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Enhanced S-Cone syndrome. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate.
GeneDx	RCV001045323	SCV001813632	pathogenic	not provided	2025-03-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19823680, 19898638, 27013732, 28418496, 10655056, 30324420, 19718767, 34426522, 31980526, 32679203, 32531858, 28559085, 26667666, 37222315, 38317096, 31964843, 37734845, 34321860)
Revvity Omics, Revvity	RCV001045323	SCV002018368	pathogenic	not provided	2022-09-12	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000005867	SCV002556562	likely pathogenic	Enhanced S-cone syndrome	2021-02-03	criteria provided, single submitter	clinical testing	PS3
Baylor Genetics	RCV000005867	SCV004191582	pathogenic	Enhanced S-cone syndrome	2024-03-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075864	SCV005070283	pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786237	SCV005399272	likely pathogenic	Retinitis pigmentosa 37	2019-08-28	criteria provided, single submitter	clinical testing	A homozygous missense variant was identified, NM_014249.3(NR2E3):c.227G>A in exon 2 of 8 of the NR2E3 gene. This substitution is predicted to create a minor amino acid change from an arginine to glutamine at position 76 of the protein, NP_055064.1(NR2E3):p.(Arg76Gln). The arginine at this position has moderate conservation (100 vertebrates, UCSC). It is located within the NR_DBD_like domain and is a putative DNA binding site. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD). The variant is present in the gnomAD population database at a frequency of 0.02% (56 heterozygotes, 0 homozygotes). An alternative residue change at the same location to a tryptophan has been reported in the gnomAD database at a frequency of 0.003% (9 heterozygote, 0 homozygotes). The variant has been previously reported pathogenic in patients with retinal dystrophy (Li L. et al. (2017); Murro, V. et al. (2019)). In addition, functional studies show that this variant increased NR2E3 dimer formation, decreased NR2E3-CRX interaction, abolished DNA binding and impaired transcriptional activity of NR2E3 (Roduit R. et al. (2009)). A different variant in the same codon resulting in a change to tryptophan has been shown to cause enhanced S-cone syndrome (ClinVar). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.
Fulgent Genetics, Fulgent Genetics	RCV000668029	SCV005631010	pathogenic	Enhanced S-cone syndrome; Retinitis pigmentosa 37	2024-04-02	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000668029	SCV006055852	pathogenic	Enhanced S-cone syndrome; Retinitis pigmentosa 37	2023-06-01	criteria provided, single submitter	research
OMIM	RCV000005867	SCV000026049	pathogenic	Enhanced S-cone syndrome	2000-02-01	no assertion criteria provided	literature only
Counsyl	RCV000668029	SCV000792572	uncertain significance	Enhanced S-cone syndrome; Retinitis pigmentosa 37	2017-07-10	flagged submission	clinical testing
Clinical Genetics, Academic Medical Center	RCV001045323	SCV001925426	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001045323	SCV001951208	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001045323	SCV001964451	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000261496	SCV005355300	pathogenic	NR2E3-related disorder	2024-05-16	no assertion criteria provided	clinical testing	The NR2E3 c.227G>A variant is predicted to result in the amino acid substitution p.Arg76Gln. This variant has been previously reported in individuals with enhanced S-cone syndrome or autosomal recessive retinal disease (see for example Haider et al. 2000. PubMed ID: 10655056; Li et al. 2017. PubMed ID: 28418496; Stone et al. 2017. PubMed ID: 28559085, Supplementary Table 1). An alternate nucleotide change affecting the same amino acid (c.226C>T, p.Arg76Trp) has also been reported in individuals with retinal disease (Haider et al. 2000. PubMed ID: 10655056; Ge et al. 2015. PubMed ID: 26667666; Stone et al. 2017. PubMed ID: 28559085, Supplementary Table 1). This variant is reported in 0.038% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.